EP3228650A1 - Nouveau dérivé peg - Google Patents

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EP3228650A1
EP3228650A1 EP15864609.1A EP15864609A EP3228650A1 EP 3228650 A1 EP3228650 A1 EP 3228650A1 EP 15864609 A EP15864609 A EP 15864609A EP 3228650 A1 EP3228650 A1 EP 3228650A1
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group
compound
salt
hydrogen atom
formula
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EP3228650A4 (fr
EP3228650B1 (fr
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Kiyoshi Eshima
Masakazu Fukushima
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Delta Fly Pharma Inc
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Delta Fly Pharma Inc
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    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
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    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • A—HUMAN NECESSITIES
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    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy

Definitions

  • the present invention relates to a novel PEG derivative useful as a therapeutic agent for malignant tumors, and a pharmaceutical product containing the same.
  • Cytosine derivatives such as cytarabine, 1-(2'-cyano-2'-deoxy- ⁇ -D-arabinofuranosyl)cytosine, gemcitabine, decitabine, 5-azacitidine, RX-3117 (Rexahn), and SGI-110 (Astex), have effects of inhibiting cancer DNA polymerases or regulating the cancer cell cycle (G2/M arrest), and inducing differentiation of leukemic cells.
  • cytosine derivatives are useful as therapeutic agents for malignant tumors such as acute myelogenous leukemia, acute leukemia lymphocytic, malignant lymphoma, multiple myeloma, pancreatic cancer, lung cancer, and breast cancer (Patent Literature 1, Non-Patent Literatures 1 to 3).
  • Therapy for malignant tumors using these cytosine derivatives involves administration of intravenous infusion that is usually sustained for several hours to several weeks (Non-Patent Literature 1).
  • mitomycin C is an anticancer agent used for the treatment of chronic lymphocytic leukemia, chronic myelogenous leukemia, gastric cancer, colorectal cancer, lung cancer, pancreatic cancer, liver cancer, cervical cancer, uterine cancer, head and neck tumor, and urinary bladder tumor.
  • mitomycin C is also usually subjected to everyday intravenous administration.
  • Gefitinib and erlotinib are molecular targeted anticancer agents that selectively inhibit tyrosine kinase of epithelial growth factor receptor (EGFR), and are used for, for example, non-small cell lung cancer, pancreatic cancer, glioblastosis cerebri, and head and neck squamous cell carcinoma.
  • EGFR epithelial growth factor receptor
  • lapatinib and sunitinib are also tyrosine kinase inhibitors, and are used for, for example, breast cancer.
  • these molecular targeted drugs also have a problem with adverse effects such as acute lung injury and interstitial pneumonitis.
  • Paclitaxel and docetaxel are anticancer agents used for the treatment of, for example, lung cancer, ovarian cancer, breast cancer, head and neck cancer, and progressive Kaposi's sarcoma.
  • these taxane-based anticancer agents also have adverse effects such as myelosuppression such as leukopenia, and peripheral nerve disorder, and lack water-solubility.
  • CREMOPHOR is obliged to be used as a dissolution aid, but since CREMOPHOR causes severe allergic symptoms, a pretreatment of histamine H1/H2 antagonists is indispensable, which requires complicated operations at administration in the clinical environment.
  • human serum albumin is used as a dissolution aid; however, there is a concern for risks such as lack of human serum albumin and viral infection such as AIDS.
  • anticancer agents formed from low molecular weight compounds have been clinically applied by intravenous administration or peroral administration; however, in the present circumstances they are still in low availability, and only an extremely small portion of the amount administered reaches tumors.
  • the anticancer agents are systemically distributed, which leads to systemic toxicity. Since the dosage is determined by the balance between effect and toxicity, systemic toxicity occurs. Thus, in most cases, a sufficient amount of an anticancer agent required to exhibit the drug efficacy is not administered.
  • DDS drug delivery systems
  • a liposome preparation for intravenous administration since the particle size is controlled to be 200 to 300 nm so that liposomes can pass through capillary blood vessels without any problem and can pass through new blood vessels near a tumor, and in addition to that, since the membrane surface of the liposome particles is coated with a polyethylene glycol (hereinafter, referred to as PEG) having a molecular weight of about 2,000, ingestion of the liposomes by phagocytes in vivo is generally avoided.
  • PEG polyethylene glycol
  • the inventors of the present invention paid attention to sustainability of a PEG derivative in blood and high clustering properties to tumor tissues, and in order to enhance the effect durability of an antitumor agent, the inventors conducted investigations in view of the controlled release properties in blood associated with lyases in blood, on the modification of SN-38, which is an active substance of CPT-11, by ester bonding or carbamate bonding between a hydroxyl group of SN-38 and polyethylene glycol.
  • SN-38 which is an active substance of CPT-11
  • a compound of Formula (1) in which a four-branched polyethylene glycol having a methylcarboxyl group introduced into each of the chain terminals is amide-bonded to a primary or secondary amino group of an antitumor agent such as a cytosine derivative, mitomycin C, or paclitaxel, or to a primary or secondary amino group of amolecular targeted drug for cancer, such as gefitinib, erlotinib, lapatinib, or sunitinib, directly or through an amino acid-based spacer such as ⁇ -alanine, has excellent durability of antitumor effects and high safety, and the compound provides a superior therapeutic effect for malignant tumors at a small dose and a small number of times of administration compared to conventional antitumor agents.
  • an antitumor agent such as a cytosine derivative, mitomycin C, or paclitaxel
  • amolecular targeted drug for cancer such as gefitinib, erlotinib, lapatinib
  • the present invention provides the following [1] to [11].
  • Compound (1) of the present invention has excellent anti-malignant tumor effects and has superior effect durability, Compound (1) exhibits excellent anti-malignant tumor activity at a small dose (as converted to the active substance of the original antitumor agent), a small number of times of administration, and a low frequency of administration compared to conventional antitumor agents, and also has reduced adverse effects. Therefore, when a treatment for a malignant tumor using Compound (1) of the present invention is employed, the burden of patients and the burden of physicians are both reduced, and excellent anti-malignant tumor effects are obtained.
  • R 1 represents a single bond, -N(R 3 ) (CH 2 ) n1 CO-, or -N(R 4 ) (CH 2 ) n2 N(R 5 )CO(CH 2 ) n3 CO-, wherein R 3 represents a hydrogen atom or an alkyl group; R 4 and R 5 , which may be identical or different from each other, each represent a hydrogen atom or an alkyl group, or R 4 and R 5 are bonded together and represent an alkylene group having 1 to 4 carbon atoms; and n1, n2, and n3, which may be identical or different from each other, each represent an integer of from 1 to 3.
  • the group of R 3 , R 4 or R 5 is preferably a hydrogen atom, and when the group is an alkyl group, the alkyl group may be a linear or branched alkyl group having 1 to 6 carbon atoms. Above all, a linear or branched alkyl group having 1 to 4 carbon atoms is preferred, and for example, a methyl group, an ethyl group, and an isopropyl group are more preferred.
  • the alkylene group having 1 to 4 carbon atoms that is formed by R 4 and R 5 together may be a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, and an ethylene group is more preferred.
  • R 3 is more preferably a hydrogen atom.
  • R 4 and R 5 it is more preferable that both represent a hydrogen atom, or R 4 and R 5 form a C 1-3 alkylene group.
  • n1, n2 and n3 each represent an integer of 1, 2, or 3, and among these, 2 is more preferable.
  • R 1 More preferred examples of R 1 include a single bond, -NH(CH 2 ) n1 CO-, -NH(CH 2 ) n2 NHCO(CH 2 ) n3 CO-, and
  • R 1 includes a single bond, -NHCH 2 CH 2 CO- and
  • R 2 represents a group of Formula (a), (b), (c), (d), (e), or (f): wherein R 6 represents a hydroxyl group, a cyano group, or a halogen atom; R 7 represents a hydrogen atom or a halogen atom; R 8 represents a hydrogen atom or an ethynyl group; R 9 and R 10 , which are identical or different from each other, each represent a hydrogen atom or a trialkylsilyl group, or R 9 and R 10 are bonded together and represent a tetraalkylsiloxysilyl group; R 11 represents a halogen atom or an ethynyl group; R 12 represents a hydrogen atom or a halogen atom; R 13 represents an alkyl group or an alkoxyalkyl group; R 14 represents an alkoxyalkyl group or a morpholinoalkyl group; R 15 represents an alkyl group; R 16 represents a hydrogen atom or an al
  • R 6 represents a hydroxyl group, a cyano group, or a halogen atom; however, a cyano group is particularly preferred.
  • R 7 represents a hydrogen atom or a halogen atom.
  • the halogen atom is preferably a fluorine atom.
  • R 8 represents a hydrogen atom or an ethynyl group.
  • Examples of the trialkylsilyl group of R 9 or R 10 include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylbutylsilyl group, and a dimethylpentylsilyl group.
  • the tetraalkylsiloxysilyl group formed by R 9 and R 10 together is preferably a group of the following Formula (g): wherein R 17 , R 18 , R 19 , and R 20 each represent an alkyl group, and for example, a methyl group, an ethyl group, an isopropyl group, a butyl group, and a pentyl group are preferred.
  • R 11 represents a halogen atom or an ethynyl group.
  • R 12 represents a hydrogen atom or a halogen atom.
  • R 13 represents an alkyl group or an alkoxyalkyl group.
  • the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group.
  • a C 1-6 alkoxy-C 1-6 alkyl group is preferred; for example, a methoxyethyl group, a methoxypropyl group, and an ethoxyethyl group are more preferred; and a methoxyethyl group is particularly preferred.
  • R 14 represents an alkoxyalkyl group or a morpholinoalkyl group.
  • the alkoxyalkyl group is preferably a C 1-6 alkoxy-C 1-6 alkyl group; more preferably a methoxyethyl group, a methoxypropyl group, or an ethoxyethyl group; and particularly preferably a methoxyethyl group.
  • the morpholinoalkyl group is preferably a morpholino-C 1-4 alkyl group, and more preferably a morpholinopropyl group.
  • R 15 is preferably a C 1-6 alkyl group; and more preferably a methyl group, an ethyl group, a propyl group, or a butyl group.
  • R 16 is preferably a hydrogen atom or an alkanoyl group having 2 to 6 carbon atoms; and more preferably a hydrogen atom or an acetyl group.
  • the group of Formula (a), (b), (c), (d), (e), or (f) is a group derived from an anticancer agent.
  • Formula (a) represents a group derived from an arabinofuranosylcytosine-based anticancer agent.
  • Formula (b) represents a group derived from mitomycin C.
  • Formula (c) represents a group derived from an EGFR tyrosine kinase inhibitor such as gefinitib or erlotinib.
  • Formula (d) represents a group derived from a PDGFR tyrosine kinase inhibitor such as sunitinib.
  • Formula (e) represents a group derived from an EGFR tyrosine kinase inhibitor such as lapatinib.
  • Formula (f) represents a group derived from a taxane-based anticancer agent such as paclitaxel or docetaxel.
  • Preferred examples of the structure of Formula (a) include ⁇ -D-arabinofuranosylcytosine, 2'-cyano-2'-deoxy- ⁇ -D-arabinofuranosylcytosine, 2'-deoxy-2',2'-difluoro- ⁇ -D-arabinofuranosylcytosine, and 3'-ethynyl- ⁇ -D-arabinofuranosylcytosine.
  • group of Formula (c) include a group of Formula (c1) and a group of Formula (c2):
  • group of Formula (f) include a group of Formula (f1) and a group of Formula (f2): m represents a number of from 10 to 1, 000. Amore preferred value of m is from 100 to 500, and an even more preferred value of m is from 200 to 300. m represents a number originating from a polyethylene glycol group, and is usually an average value.
  • the salt of Compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, and nitrate; and organic acid salts such as acetate, citrate, tartrate, oxalate, and malate. Since Compound (1) of the present invention or a salt thereof has an asymmetric carbon atom, there are steric isomers, and optically active substances thereof, enantiomers, and mixtures thereof are included.
  • Compound (1) of the present invention or a salt thereof can be produced by, for example, the following reaction scheme: wherein X represents a hydroxyl group, a halogen atom, or an active ester residue of a carboxyl group; and R 1 , R 2 , and m respectively have the same meanings as described above.
  • Compound (1) of the present invention or a salt thereof can be produced by bonding a carboxyl group of a tetracarboxylic acid derivative of Formula (2) to an amino group of a compound of Formula (3).
  • the tetracarboxylic acid derivative (2) is obtained by, for example, reacting pentaerythritol with ethylene oxide, subsequently carboxymethylating the reaction product, and further halogenating or active esterifying a carboxyl group.
  • the halogen atom include a chlorine atom and a bromine atom.
  • the active ester include succinimide and a mixed acid anhydride.
  • a compound in which R 1 represents -N(R 3 ) (CH 2 ) n1 CO- or -N(R 4 ) (CH 2 ) n2 N(R 5 ) CO (CH 2 ) n3 CO- is obtained by, for example, reacting a Compound (3) in which R 1 represents a single bond, with HN(R 3 ) (CH 2 ) n1 COY or HN(R 4 ) (CH 2 ) n2 N(R 5 )CO (CH 2 ) n3 COY.
  • R 3 , R 4 , R 5 , n1, n2, and n3 respectively have the same meanings as described above; and Y represents a hydroxyl group, a halogen atom, or an active ester residue.
  • This reaction is a carboxylic acid amide-forming reaction, and can be carried out using a condensing agent such as HBTU or DCC in the presence of a base.
  • the reaction between the tetracarboxylic acid derivative (2) and the Compound (3) is a carboxylic acid amide-forming reaction, and can be carried out under conventional amidation reaction conditions.
  • the reaction can be carried out under the conditions of from 0°C to 150°C in the presence of an amine such as triethylamine or N,N-dimethylaniline.
  • the target material can be purified and isolated by means of washing, recrystallization, and various chromatographic means.
  • Compound (1) of the present invention or a salt thereof has excellent anti-malignant tumor activity and has reduced adverse effects such as body weight reduction, and excellent anti-malignant tumor effects are obtained without requiring sustained infusion that lasts several hours or longer. Therefore, the Compound (1) or a salt thereof is useful as an excellent therapeutic agent for a malignant tumor with reduced burden for patients and physicians.
  • Compound (1) of the present invention or a salt thereof is such that there is only an amide bond as the bond between PEG and the anticancer agent, and thus the compound or the salt can avoid rapid decomposition by lyases in blood, such as esterases or carboxylases.
  • the Compound (1) or the salt has a very small molecular size per se, is not likely to be attacked by phagocytes due to the characteristics of PEG, and is very stable in blood.
  • the renal excretion rate is also very low due to the large molecular weight, targeting to a tumor is highly efficient.
  • the dosage can be extremely lowered compared to the case of conventional low molecular weight anticancer agents that have been administered by methods such as intravenous administration or oral administration.
  • the duration of administration per time can be in around 30 minutes for an anticancer agent that has been conventionally relied on long-time sustained infusion.
  • Examples of the malignant tumor that becomes an object of application of the Compound (1) of the present invention or a salt thereof include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gall bladder and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, renal cancer, urinary bladder cancer, prostate cancer, testicular tumor, bone and soft tissue sarcomas, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, and mesothelial tumor.
  • a pharmaceutical composition of various forms can be produced by mixing the compound or the salt with a pharmaceutically acceptable carrier as necessary.
  • a pharmaceutically acceptable carrier examples include a peroral agent, an injectable preparation, a suppository, a patch, and an ointment; however, it is preferable to prepare the compound or the salt as an injectable preparation.
  • various organic or inorganic carrier materials that are conventionally used as preparation materials are used, and the carrier is incorporated as an excipient, a binder, a disintegrant, a lubricating agent, or a colorant for solid preparations; and as a solvent, a dissolution aid, a suspending agent, an isotonic agent, abuffer agent, or a soothing agent for liquidpreparations .
  • preparation additives such as an antiseptic agent, an antioxidant, a colorant, a sweetening agent, and a stabilizer can also be used as necessary.
  • an oral solid preparation for example, an excipient, or an excipient, a binder, a disintegrant, a lubricating agent, a colorant, and a flavoring agent/corrigent are added to the Compound (1) of the present invention, and then for example, tablets, coated tablets, a granular preparation, a powder, and capsules can be produced by conventional methods.
  • an injectable preparation for example, a pH adjusting agent, a buffer agent, a stabilizer, an isotonic agent, and a local anesthetic agent are added to the Compound (1) of the present invention, and a subcutaneous injectable preparation, an intramuscular injectable preparation, and an intravenous injectable preparation can be produced by conventional methods.
  • the medicine of the present invention is used for the treatment of a malignant tumor in the blood system, it is preferable that the medicine is administered by means of intravenous administration within one hour, or by means of intravenous drip infusion within several hours after diluting the medicine with physiological saline or a glucose infusion solution.
  • pancreatic cancer cells 5 ⁇ 10 6 cells of pancreatic cancer cells were transplanted into the right abdomen of a BALB/c nude mouse, and after 7 days, at the time point at which the average tumor size reached 100 mm 3 , drug administration was initiated. Up to 29 days from the time of drug administration, the body weight of the mouse and the tumor volume were measured. The results are presented in Fig. 11, Fig. 12 , and Table 1. Subcutaneous continuous infusion of 1-(2'-cyano-2'-deoxy- ⁇ -D-arabinofuranosyl)cytosine hydrochloride (DFP-10917) at a dose of 4.5 mg/kg/day was continuously performed for two weeks using a micropump embedded in the body of the mouse.
  • DFP-10917 1-(2'-cyano-2'-deoxy- ⁇ -D-arabinofuranosyl)cytosine hydrochloride
  • Compound (1a) was intravenously administered once a week at a dose of 100 mg/kg, 200 mg/kg, or 300 mg/kg.
  • the dosage of this Compound (1a) is administration once a week at a dose of 2.4 mg/kg, 4.8 mg/kg, or 7.2 mg/kg, as converted to DFP-10197.
  • Mitomycin C MMC
  • Compound (1e) was intravenously administered once a week at a dose of 25 mg/kg, 50 mg/kg, 100 mg/kg, or 200 mg/kg.
  • the dose of this Compound (1e) was administration once a week at a dose of 0.8 mg/kg, 1.7 mg/kg, 3.3 mg/kg, or 6.7 mg/kg, as converted to MMC.
  • Compound (1a) was intravenously administered once a week at a dose of 200 mg/kg (the amount as converted to DFP-10917 was 4.8 mg/kg), and pemetrexed, which is a standard drug for lung cancer, was intraperitoneally administered once a week at a dose of 300 mg/kg.
  • physiological saline was intravenously administered once a week. The observation was made for two weeks (administered two times in total).
  • Compound (1g) exhibited an antitumor effect that was about 1/2 of the effect of gemcitabine, despite that Compound (1g) was administered at a dose of from 1/35 to 1/40 as converted to gemcitabine, relative to the dose of gemcitabine itself.
  • Human lung cancer cell A549 cells were transplanted into the right abdomen of a BALB/c nude mouse, and after 11 days, at the time point at which the average tumor size reached 200 mm 3 , drug administration was initiated.
  • the dosage schedule is presented in Table 5 and Table 6.
  • Compound (1h) exhibited an antitumor effect equivalent to that of the de-ethylated form of sunitinib, at a dose of from 4/50 to 8/50 as converted to sunitinib, relative to the dose of sunitinib.
  • Compound (1i) exhibited an antitumor effect superior to lapatinib at a dose of from 11.6/100 to 17.4/100 as converted to lapatinib, relative to the dose of lapatinib.
  • Compound (1j) exhibited a tumor growth inhibition ratio of 36% to 37.5%, and exhibited an effect equivalent or superior to that of paclitaxel as the control, which gave a tumor growth inhibition ratio of 29.8%.
  • Compound (1j) is a compound which can achieve an excellent balance between efficacy and safety, and that Compound (1j) also has high water-solubility per se, so that the compound can be a new therapeutic agent for a malignant tumor, which can significantly improve the means for administration in clinical settings, compared to paclitaxel that is sparingly soluble in water.

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RU2017122971A (ru) 2019-01-09
JPWO2016088858A1 (ja) 2017-09-07
EP3228650A4 (fr) 2018-10-17
PL3228650T3 (pl) 2022-06-27
WO2016088858A1 (fr) 2016-06-09
CN107001617B (zh) 2019-08-27
US10111955B2 (en) 2018-10-30
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JP6542799B2 (ja) 2019-07-10
ES2910659T3 (es) 2022-05-13
CN107001617A (zh) 2017-08-01
US20170368177A1 (en) 2017-12-28
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EP3228650B1 (fr) 2022-03-09

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